Field of the Invention
This invention relates to compounds and pharmaceutical compositions comprising such compounds which inhibit cellular xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease.
Reference
The following publications, patents and patent applications are cited in this application as superscript numbers:
1Glenner, et al., xe2x80x9cAlzheimer""s Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Proteinxe2x80x9d, Biochem. Biophys. Res. Commun., 120:885-890 (1984).
2Glenner, et al., xe2x80x9cPolypeptide Marker for Alzheimer""s Disease and its Use for Diagnosisxe2x80x9d, U.S. Pat. No. 4,666,829 issued May 19, 1987.
3Selkoe, xe2x80x9cThe Molecular Pathology of Alzheimer""s Diseasexe2x80x9d, Neuron, 6:487-498 (1991).
4Goate, et al., xe2x80x9cSegregation of a Missense Mutation in the Amyloid Precursor Protein Gene with Familial Alzheimer""s Diseasexe2x80x9d, Nature, 349:704-706 (1990).
5Chartier-Harlan, et al., xe2x80x9cEarly-Onset Alzheimer""s Disease Caused by Mutations at Codon 717 of the xcex2-Amyloid Precursor Proteing Genexe2x80x9d, Nature, 353:844-846 (1989).
6Murrell, et al., xe2x80x9cA Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer""s Diseasexe2x80x9d, Science, 254:97-99 (1991).
7Mullan, et al., xe2x80x9cA Pathogenic Mutation for Probable Alzheimer""s Disease in the APP Gene at the N-Terminus of xcex2-Amyloid, Nature Genet., 1:345-347 (1992).
8Schenk, et al., xe2x80x9cMethods and Compositions for the Detection of Soluble xcex2-Amyloid Peptidexe2x80x9d, International Patent Application Publication No. WO 94/10569, published May 11, 1994.
9Selkoe, xe2x80x9cAmyloid Protein and Alzheimer""s Diseasexe2x80x9d, Scientific American, pp. 2-8, November, 1991.
10Losse, et al., Tetrahedron, 27:1423-1434 (1971).
11Citron, et al., xe2x80x9cMutation of the xcex2-Amyloid Precursor Protein in Familial Alzheimer""s Disease Increases P-Protein Production, Nature, 360:672-674 (1992).
12Hansen, et al., xe2x80x9cReexamination and Further Development of a Precise and Rapid Dye Method for Measuring Cell Growth/Cell Killxe2x80x9d, J. Immun. Meth., 119:203-210 (1989).
13P. Seubert, Nature (1992) 359:325-327
14Johnson-Wood et al., PNAS USA (1997) 94:1550-1555
15 Tetrahedron Letters, 34(48), 7685 (1993))
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
State of the Art
Alzheimer""s Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down""s Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the xcex2-amyloid peptide (xcex2AP) or sometimes Axcex2, Axcex2P or xcex2/A4. xcex2-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,8292.
Molecular biological and protein chemical analyses have shown that the xcex2-amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding the APP has demonstrated that xcex2-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). The precise biochemical mechanism by which the xcex2-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of xcex2-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe3. The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al.4; Chartier-Harlan, et al.5; and Murrell, et al.6) and is referred to as the Swedish variant. A double mutation changing lysine595-methionine596 to asparagine595-leucine596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the xcex2-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its xcex2-amyloid peptide fragment can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other xcex2-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting xcex2-amyloid peptide release and/or its synthesis in vivo.
This invention is directed to the discovery of a class of compounds which inhibit xcex2-amyloid peptide release and/or its synthesis and, therefore, are useful in the prevention of AD in patients susceptible to AD and/or in the treatment of patients with AD in order to inhibit further deterioration in their condition. The class of compounds having the described properties are selected from the generic formulas I-IV below: 
wherein R1 is selected from the group consisting of:
(a) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and heteroaryl,
(b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and heteroaryl,
(c) cycloalkenyl,
(d) substituted alkyl provided that the substituent is not aryl and/or heteroaryl groups,
(e) substituted alkenyl provided that the substituent is not aralkenyl or heteroaralkenyl,
(f) substituted alkynyl provided that the substituent is not aralkynyl or heteroaralkynyl, and
(h) heterocyclic;
R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
X is xe2x80x94C(O)Y or xe2x80x94C(S)Y where Y is selected from the group consisting of
(a) alkyl or cycloalkyl,
(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include xcex1-haloalkyl, xcex1-diazoalkyl, xcex1-OC(O)alkyl or xcex1-OC(O)aryl groups,
(c) alkoxy or thioalkoxy,
(d) substituted alkoxy or substituted thioalkoxy,
(e) hydroxy,
(f) aryl,
(g) heteroaryl,
(h) heterocyclic,
(i) xe2x80x94NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of Rxe2x80x2 or Rxe2x80x3 is hydroxy or alkoxy, and where Rxe2x80x2 and Rxe2x80x3 are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,
(j) xe2x80x94NHSO2xe2x80x94R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
(k) xe2x80x94NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and
(l) xe2x80x94ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
X can also be xe2x80x94CR6R6Yxe2x80x2 where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Yxe2x80x2 is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, phthalimido, xe2x80x94OC(O)R7, xe2x80x94SSR7, xe2x80x94SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
Xxe2x80x2 is hydrogen, hydroxy or fluoro;
Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an
oxo group, and
n is an integer equal to 1 or 2;
with the proviso excluding the following known compound:
when R1 is o-fluorophenyl, R2 is 3,4-dichlorophenyl or ethyl, R4 and R5 are hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, then X is not xe2x80x94C(O)OCH3; 
wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
R2 is selected from the group consisting of
(a) substituted alkyl provided that such substituted alkyl groups do not include aryl or heteroaryl substituted alkyl or a side-chain of a naturally occurring amino acid,
(b) substituted alkenyl provided that such substituted alkenyl groups do not include aryl or heteroaryl substituted alkenyl,
(c) substituted alkynyl provided that such substituted alkynyl groups do not include aryl or heteroaryl substituted alkynyl,
(d) heterocyclic,
(e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, and heteroaryl, and
(f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;
each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
X is xe2x80x94C(O)Y or xe2x80x94C(S)Y where Y is selected from the group consisting of
(a) alkyl or cycloalkyl,
(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include xcex1-haloalkyl, xcex1-diazoalkyl, xcex1-OC(O)alkyl or xcex1OC(O)aryl groups,
(c) alkoxy or thioalkoxy,
(d) substituted alkoxy or substituted thioalkoxy,
(e) hydroxy,
(f) aryl,
(g) heteroaryl,
(h) heterocyclic,
(i) xe2x80x94NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of Rxe2x80x2 or Rxe2x80x3 is hydroxy or alkoxy, and where Rxe2x80x2 and Rxe2x80x3 are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,
(j) xe2x80x94NHS2xe2x80x94R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
(k) xe2x80x94NR9NR10N10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and
(l) xe2x80x94ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
X can also be xe2x80x94CR6R6Yxe2x80x2 where each R6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Yxe2x80x2 is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, xe2x80x94OC(O)R7, xe2x80x94SSR7, xe2x80x94SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
Xxe2x80x2 is hydrogen, hydroxy or fluoro;
Xxe2x80x2 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group, and
n is an integer equal to 1 or 2; 
wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl provided that at least one R4 is selected to be:
(a) substituted alkyl provided that such substituted alkyl groups do not include aryl or heteroaryl substituted alkyl or a side-chain of a naturally occurring amino acid,
(b) substituted alkenyl provided that such substituted alkenyl groups do not include aryl or heteroaryl substituted alkenyl,
(c) substituted alkynyl provided that such substituted alkynyl groups do not include aryl or heteroaryl substituted alkynyl,
(d) heterocyclic,
(e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, and heteroaryl, and
(f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy, thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;
each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
X is xe2x80x94C(O)Y or xe2x80x94C(S)Y where Y is selected from the group consisting of
(a) alkyl or cycloalkyl,
(b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include xcex1-haloalkyl, xcex1-diazoalkyl, xcex1-OC(O)alkyl or xcex2-OC(O)aryl groups,
(c) alkoxy or thioalkoxy,
(d) substituted alkoxy or substituted thioalkoxy,
(e) hydroxy,
(f) aryl,
(g) heteroaryl,
(h) heterocyclic,
(i) xe2x80x94NRxe2x80x2 Rxe2x80x3 where R1 and Rxe2x80x3 are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of Rxe2x80x2 or Rxe2x80x3 is hydroxy or alkoxy, and where Rxe2x80x2 and Rxe2x80x3 are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,
(j) xe2x80x94NHSO2xe2x80x94R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
(k) xe2x80x94NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclic, and
(l) xe2x80x94ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
X can also be xe2x80x94CR6R6Yxe2x80x2 where each R6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Yxe2x80x2 is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, xe2x80x94OC(O)R7, xe2x80x94SSR7, xe2x80x94SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
Xxe2x80x2 is hydrogen, hydroxy or fluoro;
Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group, and
n is an integer equal to 1 or 2; and 
wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic;
R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic;
each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
X is selected from the group consisting of
(a) xe2x80x94C(O)-alkyl,
(b) xe2x80x94C(O)-substituted alkoxy or substituted thioalkoxy provided that the substituted alkoxy groups do not include benzyl and phenethyl,
(c) xe2x80x94C(O)-aryl wherein the aryl group is substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, heteroaryl, and trihalomethyl,
(d) xe2x80x94C(O)-heteroaryl wherein the heteroaryl group is substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, aryl, alkaryl, aryloxy, halo, nitro, heteroaryl, thioalkoxy and thioaryloxy
(e) xe2x80x94C(O)-NRxe2x80x2 Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, heterocyclic, where one of Rxe2x80x2 or Rxe2x80x3 is hydroxy or alkoxy, and where Rxe2x80x2 and Rxe2x80x3 are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and
X can also be xe2x80x94CR6R6Yxe2x80x2 where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Yxe2x80x2 is selected from the group consisting of amino, thiol, alkoxy, phthalimido, xe2x80x94OC(O)R7, xe2x80x94SSR7, xe2x80x94SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic,
provided that Rxe2x80x2 and Rxe2x80x3 are not both independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl;
Xxe2x80x2 is hydrogen, hydroxy or fluoro;
Xxe2x80x3 is hydrogen, hydroxy or fluoro, or Xxe2x80x2 and Xxe2x80x3 together form an oxo group, and
n is an integer equal to 1 or 2;
with the proviso that:
when R1 is iso-propyl, R2 is phenyl, R4is methyl, R5 is hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, n is 2, and the second R4 at the carboxy terminus is methyl, then X is not xe2x80x94C(O)NH-pNO2xe2x80x94xcfx86;
with the additional provisos that in compounds selected from formulas I-IV:
A. when R1 is phenyl, R2 is methyl, R4 is xe2x80x94CH(OH)CH3 derived from D-threonine, R5 is hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, and n is 1, then X is not xe2x80x94C(O)OH or xe2x80x94C(O)OCH3;
B. when R1 is 3-nitrophenyl, R2 is methyl, R4is xe2x80x94CH(OH)CH3, R5 is hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, and n is 1, then X is not xe2x80x94C(O)NH2 or xe2x80x94CH2OH;
C. when R1 is 3,5-difluorophenyl, R2 is methyl, R4is phenyl derived from D-phenylglycine, R5 is hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, and n is 1, then X is not xe2x80x94CHOHxcfx86 or xe2x80x94CH2OH;
D. when R1 is N-(2-pyrrolidinonyl), R2 is methyl, R4is benzyl, R5 is hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, and n is 1, then X is not xe2x80x94C(O)OCH3;
E. when R1 is 3,5-difluorophenyl, R2 is methyl derived from D-alanine, R4 is phenyl derived from D-phenylglycine, R5 is hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, and n is 1, then X is not xe2x80x94C(O)NH-benzyl;
F. when R1 is 3,5-difluorophenyl, R2 is methyl, R4 is hydrogen, R5 is hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, and n is 1, then X is not xe2x80x94CH2OH;
G. when R1 is 3,5-difluorophenyl, R2 is methyl, R4is 4-phenylphenyl, R5 is hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, and n is 1, then X is not xe2x80x94C(O)NHC(CH3)3; and
H. when R1 is 3,5-difluorophenyl, R2 is methyl, R4is phenyl derived from D-phenylglycine, R5 is hydrogen, Xxe2x80x2 and Xxe2x80x3 are hydrogen, and n is 1, then X is not xe2x80x94C(O)NHCH(CH3)xcfx86.
Preferably, the compounds of this invention are derived from L-amino acids.
The compounds described above are useful for inhibiting xcex2-amyloid peptide release and/or its synthesis in a cell when administered to such a cell in an amount effective in inhibiting the cellular release and/or synthesis of xcex2-amyloid peptide.
Because the in vivo generation of xcex2-amyloid peptide is associated with the pathogenesis of AD8,9, the compounds of this invention can also be employed in conjunction with a pharmaceutical composition to prophylactically and/or therapeutically prevent and/or treat AD. When employed for prophylactic methods for preventing the onset of AD in a patient at risk for developing AD, a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of this invention above is administered to the patient.
When employed for therapeutic methods for treating a patient with AD in order to inhibit further deterioration in the condition of that patient, a pharmaceutical composition comprising a pharmaceutically inert carrier and an effective amount of a compound or a mixture of compounds of this invention above is administered to the patient.
Compounds suitable for use in the claimed methods include, by way of example only, the following:
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidine methyl ester
N-benzyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
N-2-(N,N-dimethylamino)ethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
N-(2-methoxyethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
N-2-(N,N-dimethylamino)ethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
N-(4-pyridyl)methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
N-(3-pyridyl)methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
N-(4-pyridyl)methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate tert-butyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[3-(N,N-dimethylamino)propoxy]phenylalanine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[(tert-butyloxycarbonyl)methoxy]phenylalanine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(carboxymethoxy)phenylalanine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalanine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(N,N-dimethylamino)hexanoate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propionate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)propionate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-pyridyl)propionate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionate methyl ester
N-(2-methoxyethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenylalaninamide
N-(2-methoxyethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester
N-(2-methoxyethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(4-pyridyl)propionamide
N-(2-methoxyethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-(2-pyridyl)propionamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)propionate methyl ester
N-(3-methoxybenzyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(1-naphthyl)propionate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propionate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-thienyl)propionate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine benzyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-bromo-propyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-iodopropyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine tert-butyl ester
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-Nxcex5-(tert-butoxycarbonyl)-L-lysine methyl ester
methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-4-phenylbutanoate
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 2-phenylethyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 3-phenylpropyl ester
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate ethyl ester
N-methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
N,N-dimethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-methoxyphenyl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-methoxyphenyl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate ethyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetate ethyl ester
N-[N-(cyclohex-1-enylacetyl)-L-alaninyl]-L-phenylalanine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carboxylate methyl ester
N-2-(N,N-dimethylamino)ethyl-N-methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester
N-hydroxy-Nxe2x80x2-[N-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-methoxy-N-methyl-Nxe2x80x2-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide
N-iso-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N,N-di-n-propyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamide
N-(4-nitrophenyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
N-(2-methoxyethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
N-(4-nitrobenzyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-(4-nitrophenyl)-Nxe2x80x2-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-alaninamide
N-(4-nitrophenyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
N-benzyl-N-methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-(3,5-difluorobenzyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-(3-nitrobenzyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-benzyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-(4-nitrobenzyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan methyl ester
N-(4-methoxybenzyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine methyl ester
N-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]-L-phenylglycine methyl ester
N-(2-phenylethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophanamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropionate methyl ester
N-(2-methoxyethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(4-nitrophenyl)propionamide
N-[(R)-xcex1-methylbenzyl]-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-[(S)-xcex1-methylbenzyl]-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-(4-fluorobenzyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-(4-pyridylmethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-(4-trifluoromethylbenzyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionate ethyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-cyclohexylacetate ethyl ester
N-(2-methoxyethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-2-(N,N-dimethylamino)ethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-(2-pyridylmethyl)-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-fluorophenyl)acetate ethyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-fluorophenyl)acetate ethyl ester
N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionate ethyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine neopentyl ester
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholine
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl ester
4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyryl]morpholine
4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]morpholine
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine methyl ester
N-2-methoxyethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-2-(N,N-dimethylamino)ethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-cyclohexyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-neopentyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-tetrahydrofurfuryl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-2-pyridylmethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
3-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thiazolidine
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl ester
N-(R)-sec-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
1-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidine
N-(S)-sec-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl ester
N-2-fluoroethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
N-[(S)-6-methyl-3-oxohept-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-4-nitrobenzyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutyramide
N-4-nitrobenzyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)acetate methyl ester
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophen-2-yl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2-yl)acetate ethyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-3-yl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-yl)acetate ethyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetate tert-butyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetic acid
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(1H-tetrazol-5-yl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(6-methoxy-2-naphthyl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylphenyl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydrobenzothiophen-2-yl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate methyl ester
N-[N-(3,5-difuorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazol-4-yl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate methyl ester
N-tert-butyl-Nxe2x80x2-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(4-phenylphenyl)acetamide
N-[N-(3,5-difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycine tert-Butyl Ester
N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine tert-butyl ester
N-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)glycinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine methyl ester
N-cyclohexyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-glutamide
N-[(S)-3-hydroxy-6-methylhept-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(S)-2-hydroxy-1-phenyleth-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[N-(3,5-difluorophenyl-xcex1-fluoroacetyl)-L-alaniny]-L-phenylglycine tert-butyl ester
N-[N-(3,5-difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglycine methyl ester
N-[(1R,2S)-1-hydroxy-1-phenylprop-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-2-methoxyethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide
N-[(S)-xcex1-hydroxy-xcex1-phenyl-iso-propyl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(S)-2-hydroxy-1,2-diphenylethyl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(S)-1-hydroxyhex-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[xcex1-hydroxy-xcex1xe2x80x2-(4-hydroxyphenyl)-iso-propyl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-2-pyridylmethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide
N-[xcex1-hydroxy-xcex1xe2x80x2-pyrid-2-yl-iso-propyl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[xcex1-hydroxy-xcex1xe2x80x2-pyrid-4-yl-iso-propyl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(S)-1-hydroxy-4-methylpent-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[xcex1-methoxy-prop-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[1-hydroxy-3-methyl-but-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-yl)acetate methyl ester
N-[1-hydroxy-prop-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(S)-2-methoxy-1-phenyleth-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(S)-1-methoxy-2-phenyl-prop-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(S)-1-acetoxyhex-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[2-hydroxy-1-(thien-2-yl)ethyl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[N-(3,5-difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenylalanine tert-butyl ester
N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinol
N-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butyl ester
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-2-yl)glycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(5-bromothien-2-yl)glycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-bromothien-2-yl)glycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-2-yl)glycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)glycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-3-yl)glycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(5-chlorothien-2-yl)glycinamide
N-Cyclohexyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4-(phenyl)phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)phenylglycinamide
N-(S)-(xe2x88x92)-xcex1-methylbenzyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaniny]-D,L-phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(cyclohexyl)phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylphenyl)phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(tert-butyl)phenylglycinamide
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-3-(4-chlorophenoxy)phenylglycinamide
N-cyclohexyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(phenyl)phenylglycinamide
N-[N-(3,5-difluorophenyl-xcex1-hydroxyacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester
N-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenyl-xcex1, xcex1-difluoroacetyl)-L-alaninyl]-L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine tert-butyl ester
N-[(S)-1-oxo-1-phenylprop-2-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(pyrid-3-yl)glycine tert-butyl ester
[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholine
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine N-tert-butoxycarbonyl(hydroxyl amine) ester
N-neopentyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-tetrahydrofurfuryl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-methoxy-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]azetidine
N-iso-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-cyclopropanemethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-methoxy-N-methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-2-methylprop-2-enyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-(pyrid-3-yl)methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-(pyrid-4-yl)methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-furfuryl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-cyclopentyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-1-benzylpiperidin-4-yl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N,N-dimethyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-2,2,6,6-tetramethylpiperidin-4-yl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-2-methylcyclohexyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-4-methylcyclohexyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-1-ethoxycarbonylpiperidin-4-yl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-tert-butoxy-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine N-tert-butyl(hydroxylamine) ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazide
N-(1-ethoxyethen-1-yl)-[Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazide
N-4-(phenyl)butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-3-(4-iodophenoxy)propyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-6-(amino)hexyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamide Hydrochloride
N-1-(phthalimido)pent-2-yl-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difluorophenyl)glycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine iso-propyl ester
N-(isopropyl) Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine iso-butyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophen-3-yl)acetate methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S-2-amino-3-(thiazol-4-yl)propionate tert-butyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide tert-butyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide
N-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
N-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-furanyl)acetamide
Nxe2x80x2-[N-(3,5-difuorophenylacetyl)-D-alaninyl]-D-phenylglycinamide
Nxe2x80x2-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-methylsulfonamide
Nxe2x80x3-methyl-Nxe2x80x3-phenyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide
Nxe2x80x3-methyl-Nxe2x80x3-phenyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamide
Nxe2x80x3-methyl-Nxe2x80x3-benzyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide
Nxe2x80x3-4-fluorobenzyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycine neopentyl ester
N-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine tert-butyl ester
N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-threoninyl]-L-phenylglycine methyl ester
N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methyl ester
Nxe2x80x3-4-methylphenyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
Nxe2x80x3-tetrahydrofurfuryl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamide
N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamide N-[(R)-xcex1-methylbenzyl]-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-[1-phenyl-2-oxo-3-methylbutan-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[1-phenyl-2-oxo-propan-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[1-phenyl-2-oxo-pentan-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-Nxe2x80x2-(3,5-difluorophenyl-acetyl)-L-alaninamide
N-[1-phenyl-2-oxo-butan-1-yl]-Nxe2x80x2-(3,5-difluorophenyl-acetyl)-L-alaninamide
N-[1-phenyl-2-oxo-4-methylpentan-1-yl]-Nxe2x80x2-(3,5-difluorophenyl-acetyl)-L-alaninamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-xcex1-hydroxyphenylalanine methyl ester
Nxe2x80x3-[4-((2-hydroxy-4-azido)-phenyl)-NHC(O)-)butyl]-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
N-[(S)-1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-Nxe2x80x2-(3,5-difluorophenyl-acetyl)-L-alaninamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine tert-butyl ester
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycine tert-butyl ester
Nxe2x80x3-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-n-butylphenylglycinamide
Nxe2x80x3-tert-butyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(phenylacetenyl)phenylglycinamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamide
N-[1,3-diphenyl-2-oxo-propan-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[1-phenyl-2-oxo-hexan-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
N-[1-phenyl-2-oxo-3-methylpentan-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
Nxe2x80x3-n-hexyl-6-biotinamidyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine
Nxe2x80x2-[N-(2-tert-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine methyl ester
Nxe2x80x3-tert-butyl Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycine methyl ester
N-[(S)-1-phenyl-2-oxo-3-phenylpropan-1-yl]-Nxe2x80x2-(3,5-difluorophenylacetyl)-L-alaninamide
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycine tert-butyl ester
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine
Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine tert-butyl ester
N-[2-hydroxy-1-(S)phenyleth-1-yl]-Nxe2x80x2-[(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alaninamide
N-[2-hydroxyeth-1-yl]-Nxe2x80x2-[(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide
Nxe2x80x2-[N-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycinetert-butyl ester
[N-(3-aminoproprionyl)-L-alaninyl]-L-phenylglycine tert-butyl ester
[N-(3-tert-butoxycarbonylamino)propionyl)-L-alaninyl]-L-phenylglycine tert-butyl ester
N-cyclohexyl-N-methyl-Nxe2x80x2-[N-(3,5-difluorophenylacetyl)-L-alaniny]-D,L-phenylglycinamide
N-cyclohexyl-N-methyl-Nxe2x80x2-[N-(3,5-difluorophenyl-xcex1-hydroxyacetyl)-L-alaninyl]-D,L-phenylglycinamide
N-cyclohexyl-Nxe2x80x2-[N-3,5-difluorophenyl-xcex1-hydroxyacetyl)-L-alaninyl]-D,L-phenylglycinamide.
The pharmaceutical compositions described above comprise a pharmaceutically inert carrier and a compound of this invention.
In the compounds above, Xxe2x80x3 is preferably hydrogen and Xxe2x80x2 is preferably hydrogen or fluoro.
Preferred R1 substituted aryl groups include, for example, monosubsti-tuted phenyls (preferably 3 or 5 substituents); disubstituted phenyls (preferably 3,5 substituents); and trisubstituted phenyls (preferably 3,4,5 substituents). Preferably, the substituted phenyl groups do not include more than 3 substituents.
Examples of substituted phenyls include, for instance, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl, 3-methoxyphenyl, 3-nitrophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-thiomethoxyphenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 2-hydroxyphenyl, 2-methylphenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-difluorophenyl, 2,3,4,5,6-pentafluorophenyl, 3,4-dibromophenyl, 3,4-dichlorophenyl, 3,4-methylene-dioxyphenyl, 3,5-difluorophenyl, 3,5-dichlorophenyl, 2,4-dichlorophenyl, and 2,5-difluorophenyl.
Preferred R1 alkaryl groups include, by way of example, benzyl, 2-phenylethyl, 3-phenyl-n-propyl, and the like.
Preferred R1 alkyl, substituted alkyl, alkenyl, cycloalkyl and cycloalkenyl groups include, by way of example, iso-propyl, n-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CH(CH2)4CH3, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclohex-1-enyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclobutyl, xe2x80x94CH2CH2-cyclohexyl, xe2x80x94CH2CH2-cyclopentyl, aminomethyl, N-tert-butoxycarbonylaminomethyl, and the like.
Preferred R1 heteroaryls and substituted heteroaryls include, by way of example, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, fluoropyridyls (including 5-fluoropyrid-3-yl), chloropyridyls (including 5-chloropyrid-3-yl), thien-2-yl, thien-3-yl, benzothiazol-4-yl, 2-phenylbenzoxazol-5-yl, furan-2-yl, benzofuran-2-yl, thionaphthen-2-yl, 2-chlorothiophen-5-yl, 3-methylisoxazol-5-yl, 2-(thiophenyl)thiophen-5-yl, 6-methoxythionaphthen-2-yl, 3-phenyl-1,2,4-thiooxadiazol-5-yl, 2-phenyloxazol-4-yl, and the like.
Preferably R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Particularly preferred R2 substituents include, by way of example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, phenyl, 4-fluorophenyl, 3,5-difluoro-phenyl, 4-methoxyphenyl, benzyl, cyclopropyl, cyclohexyl, cyclopentyl, cycloheptyl, thien-2-yl, thien-3-yl, xe2x80x94CH2CH2SCH3, xe2x80x94CH2OCH2xcfx86, xe2x80x94CH(CH3)OCH2xcfx86, xe2x80x94CH(OH)CH3, xe2x80x94CH2OH and the like. As noted below, R2 (as well as R4) is preferably the side chain of an L-amino acid.
Preferred R4 substituents include, for example, hydrogen, methyl, ethyl, iso-propyl, n-propyl, n-butyl, sec-butyl, iso-butyl, cyclopentyl, cyclohexyl, allyl, iso-but-2-enyl, 3-methylpentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-indol-3-yl, phenyl, p-(phenyl)phenyl, m-(phenyl)phenyl o-fluorophenyl, m-fluorophenyl, p-fluorophenyl, p-bromophenyl, m-methoxyphenyl, p-methoxyphenyl, phenethyl, benzyl, m-hydroxybenzyl, p-hydroxybenzyl, p-nitrobenzyl, m-trifluoromethylphenyl,p-(CH3)2NCH2CH2CH2O-benzyl, p-(CH3)3COC(O)CH2O-benzyl, p-phenylphenyl, 3,5-difluorophenyl, p-(HOOCCH2O)-benzyl, 2-aminopyrid-6-yl, 4-(N-morpholino-CH2CH2O)-benzyl, xe2x80x94CH2CH2C(O)NH2, xe2x80x94CH2-imidazol-4-yl, xe2x80x94CH2xe2x80x94(3-tetrahydrofuranyl), xe2x80x94CH2-thien-2-yl, xe2x80x94CH2-thiazol-4-yl, xe2x80x94CH2(1-methyl)cyclopropyl, xe2x80x94CH2-thien-3-yl, thien-3-yl, thien-2-yl, xe2x80x94CH2xe2x80x94C(O)O-t-butyl, xe2x80x94CH2xe2x80x94C(CH3)3, xe2x80x94CH2CH(CH2CH3)2, 2-methylcyclopentyl,-cyclohex-2-enyl, xe2x80x94CH[CH(CH3)2]COOCH3, xe2x80x94(CH2)2SCH3, xe2x80x94CH2CH2N(CH3)2, xe2x80x94CH2C(CH3)xe2x95x90CH2, xe2x80x94CH2CHxe2x95x90CHCH3 (cis and trans), xe2x80x94CH2OH, xe2x80x94CH(OH)CH3, xe2x80x94CH(O-t-butyl)CH3, xe2x80x94CH2OCH3, xe2x80x94(CH2)4NH-Boc, xe2x80x94(CH2)4NH2, xe2x80x94CH2)4N(CH3)2, xe2x80x94CH2-pyridyl (e.g., 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridyl (2-pyridyl, 3-pyridyl and 4-pyridyl), xe2x80x94CH2-naphthyl (e.g., 1-naphthyl and 2-naphthyl), xe2x80x94CH2xe2x80x94(N-morpholino), p-(N-morpholino-CH2CH2O)-benzyl, benzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, 5-chlorobenzo[b]thiophen-2-yl, 4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl, benzo[b]thiophen-3-yl, tetrazol-5-yl, 5-chlorobenzo[b]thiophen-3-yl, benzo[b]thiophen-5-yl, 6-methoxynaphth-2-yl, xe2x80x94CH2xe2x80x94N-phthalimidyl, 2-methylthiazol-4-yl, and thieno[2,3-b]thiophen-2-yl, 5-bromothien-2-yl, 4-bromothien-2-yl, 5-chlorothien-2-yl, 3-phenoxyphenyl, 2-phenoxyphenyl, 4-ethylphenyl, 2-benzylphenyl, (4-ethylphenyl)phenyl, 4-tert-butylphenyl, 4-n-butylphenyl, o-(4-chlorophenoxy)phenyl, furan-2-yl, 4-phenylacetylenylphenyl and the like.
Preferably, R5 is hydrogen. However, in another embodiment, R4 and R5 are fused to form a cycloalkyl group including, for example, cyclopropyl, cyclobutyl, and the like.
One preferred X substituent is xe2x80x94C(O)Y. Preferably Y is hydroxy, alkoxy or substituted alkoxy such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, tert-butoxy, neo-pentoxy, benzyloxy, 2-phenylethoxy, 3-phenyl-n-propoxy, 3-iodo-n-propoxy, 4-bromo-n-butoxy, xe2x80x94ONHC(O)OC(CH3)3, xe2x80x94ONHC(CH3)3 and the like. Another preferred Y group is xe2x80x94NRxe2x80x2Rxe2x80x3 where Rxe2x80x2 and Rxe2x80x3 are as defined above. Such preferred Y groups include, by way of example, amino (xe2x80x94NH2), xe2x80x94NH(iso-butyl), xe2x80x94NH(sec-butyl), N-methylamino, N,N-dimethylamino, N-benzylamino, N-morpholino, azetidino, N-thiomorpholino, N-piperidinyl, N-hexamethyleneimino, N-heptamethylene-imino, N-pyrrolidinyl, xe2x80x94NH-methallyl, xe2x80x94NHCH2xe2x80x94(faran-2-yl), xe2x80x94NHCH2-cyclopropyl, xe2x80x94NH(tert-butyl), xe2x80x94NH(p-methylphenyl), xe2x80x94NHOCH3, xe2x80x94NHCH2(p-fluorophenyl), xe2x80x94NHCH2CH2OCH3, xe2x80x94NH-cyclopentyl, xe2x80x94NH-cyclohexyl, xe2x80x94NHCH2CH2N(CH3)2, xe2x80x94NHCH2C(CH3)3, xe2x80x94NHCH2xe2x80x94(pyrid-2-yl), xe2x80x94NHCH2-(pyrid-3-yl), xe2x80x94NHCH2-(pyrid-4-yl), N-thiazolindinyl, xe2x80x94N(CH2CH2CH3)2, xe2x80x94N[CH2CH(CH3)2]2, xe2x80x94NHOH, xe2x80x94NH(p-NO2-xcfx86), xe2x80x94NHCH2(p-NO2-xcfx86), xe2x80x94NHCH2(m-NO2-xcfx86), xe2x80x94N(CH3)OCH3, xe2x80x94N(CH3)CH2-xcfx86, xe2x80x94NHCH2xe2x80x94(3,5-di-fluorophenyl), xe2x80x94NHCH2CH2F, xe2x80x94NHCH2(p-CH3Oxe2x80x94xcfx86), xe2x80x94NHCH2(mxe2x80x94CH3Oxe2x80x94xcfx86), xe2x80x94NHCH2p-CF3xe2x80x94xcfx86), xe2x80x94N(CH3)CH2CH2OCH3, xe2x80x94NHCH2CH2xcfx86, xe2x80x94NHCH(CH3)xcfx86, xe2x80x94NHCH2xe2x80x94(p-F-xcfx86), xe2x80x94N(CH3)CH2CH2N(CH3)2xe2x80x94NHCH2xe2x80x94(tetrahydrofuran-2-yl), xe2x80x94NHCH2(p-trifluoromethylphenyl), xe2x80x94NHCH2C(CH3)xe2x95x90CH2, xe2x80x94NH-[(p-benzyl)pyrid-4-yl], xe2x80x94NH-[(2,6-dimethyl)pyrid-4-yl], xe2x80x94NHxe2x80x94(2-methylcyclohexyl), xe2x80x94NHxe2x80x94(4-methylcyclohexyl), xe2x80x94NH-[N-ethoxycarbonyl]-piperidin-4-yl, xe2x80x94NHOC(CH3)3, xe2x80x94NHCH2CH2CH2CH2xe2x80x94xcfx86, xe2x80x94C(O)NH(CH2)3O-(p-CH3)xcfx86, xe2x80x94C(O)NH(CH2)6NH2, xe2x80x94NHxe2x80x94(tetrahydrofuran-2-yl), xe2x80x94N(CH3)xcfx86, xe2x80x94NH(CH2)4NHC(O)-(2-hydroxy-4-azido)-phenyl, xe2x80x94NH(CH2)6xe2x80x94(biotinamidyl), and the like.
Another preferred Y group is an alkyl group such as methyl, ethyl, iso-propyl, n-propyl, iso-butyl, n-butyl, sec-butyl, tert-butyl, xe2x80x94CH2CH2CH(CH3)2, xe2x80x94CH2-pyridy-2-yl, xe2x80x94CH2-pyridy-3-yl, xe2x80x94CH2-pyridy-4-yl, xe2x80x94CH2-fur-2-yl, and the like; a substituted alkyl group such as benzyl; a cycloalkyl group such as cyclopentyl; and an aryl group such as phenyl.
Still another preferred Y group is xe2x80x94NHSO2xe2x80x94R where R is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, aryl, heteroaryl and heterocyclic. Such groups are exemplified by NHxe2x80x94SO2xe2x80x94CH3.
Preferred Yxe2x80x2 groups include a substituted alkyl group such as xe2x80x94CH2OH, xe2x80x94CH(OH)CH2CH2CH(CH3)2, xe2x80x94CH(OH)xcfx86, xe2x80x94CH(OH)CH2C(O)OCH3, xe2x80x94C(OH)(CH3)2, xe2x80x94CH2OCH3, xe2x80x94CH2OC(O)OCH3, xe2x80x94CH2OC(O)C(CH3)3, and the like.
Preferred compounds for use in the methods of this invention include those set forth in the tables below:
As above, this invention relates to methods for inhibiting xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease. However, prior to describing this invention in further detail, the following terms will first be defined.
The term xe2x80x9cxcex2-amyloid peptidexe2x80x9d refers to a 39-43 amino acid peptide having a molecular weight of about 4.2 kD, which peptide is substantially homologous to the form of the protein described by Glenner, et al.1 including mutations and post-translational modifications of the normal xcex2-amyloid peptide. In whatever form, the xcex2-amyloid peptide is an approximate 39-43 amino acid fragment of a large membrane-spanning glycoprotein, referred to as the xcex2-amyloid precursor protein (APP). Its 43-amino acid sequence is:
1
Asp Ala Glu Phe Arg His Asp Ser Gly Tyr
11
Glu Val His His Gln Lys Leu Val Phe Phe
21
Ala Glu Asp Val Gly Ser Asn Lys Gly Ala
31
Ile Ile Gly Leu Met Val Gly Gly Val Val
41
Ile Ala Thr (SEQ ID NO: 1)
or a sequence which is substantially homologous thereto.
xe2x80x9cAlkylxe2x80x9d refers to monovalent alkyl groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-hexyl, and the like.
xe2x80x9cSubstituted alkylxe2x80x9d refers to an alkyl group, preferably of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, aryloxy, heteroaryloxy, heterocyclyloxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxylalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
xe2x80x9cAlkylenexe2x80x9d refers to divalent alkylene groups preferably having from 1 to 10 carbon atoms and more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methylene (xe2x80x94CH2xe2x80x94), ethylene (xe2x80x94CH2CH2xe2x80x94), the propylene isomers (e.g., xe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94CH(CH3)CH2xe2x80x94), and the like.
xe2x80x9cAlkarylxe2x80x9d refers to -alkylene-aryl groups preferably having from 1 to 10 carbon atoms in the alkylene moiety and from 6 to 10 carbon atoms in the aryl moiety. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.
xe2x80x9cAlkoxyxe2x80x9d refers to the group xe2x80x9calkyl-O-xe2x80x9d. Preferred alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
xe2x80x9cSubstituted alkoxyxe2x80x9d refers to the group xe2x80x9csubstituted alkyl-O-xe2x80x9d where substituted alkyl is as defined above.
xe2x80x9cAlkylalkoxyxe2x80x9d refers to the group xe2x80x9c-alkylene-O-alkylxe2x80x9d where alkylene and alkyl are as defined above. Such groups include, by way of example, methylenemethoxy (xe2x80x94CH2OCH3), ethylenemethoxy (xe2x80x94CH2CH2OCH3), n-propylene-iso-propoxy (xe2x80x94CH2CH2CH2OCH(CH3)2), methylene-t-butoxy (xe2x80x94CH2xe2x80x94Oxe2x80x94C(CH3)3) and the like.
xe2x80x9cAlkylthioalkoxyxe2x80x9d refers to the group xe2x80x9c-alkylene-S-alkylxe2x80x9d wherein alkylene and alkyl are as defined above. Such groups include, by way of example, methylthiomethoxy (xe2x80x94CH2SCH3), ethylthiomethoxy (xe2x80x94CH2CH2SCH3), n-propyl-iso-thiopropoxy (xe2x80x94CH2CH2CH2SCH(CH3)2), methylthio-t-butoxy (xe2x80x94CH2SC(CH3)3) and the like.
xe2x80x9cAlkenylxe2x80x9d refers to alkenyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkenyl unsaturation. Preferred alkenyl groups include ethenyl (xe2x80x94CHxe2x95x90CH2), n-propenyl (xe2x80x94CH2CHxe2x95x90CH2), iso-propenyl (xe2x80x94C(CH3)xe2x95x90CH2), but-2-enyl (xe2x80x94CH2CHxe2x95x90CHCH3), and the like.
xe2x80x9cSubstituted alkenylxe2x80x9d refers to an alkenyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
xe2x80x9cAlkynylxe2x80x9d refers to alkynyl groups preferably having from 2 to 10 carbon atoms and more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sites of alkynyl unsaturation. Preferred alkynyl groups include ethynyl (xe2x80x94Cxe2x89xa1CH), propargyl (xe2x80x94CH2Cxe2x89xa1CH) and the like.
xe2x80x9cSubstituted alkynylxe2x80x9d refers to an alkynyl group as defined above having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, halogen, hydroxyl, carboxyl, carboxylalkyl, cycloalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkyoxy, aryl, heteroaryl, heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic.
xe2x80x9cAcylxe2x80x9d refers to the groups alkyl-C(O)xe2x80x94, substituted alkyl-C(O)xe2x80x94, cycloalkyl-C(O)xe2x80x94, aryl-C(O)xe2x80x94, heteroaryl-C(O)xe2x80x94 and heterocyclic-C(O)xe2x80x94 where alkyl, substituted alkyl, cycloalkyl, aryl, heteroayl and heterocyclic are as defined herein.
xe2x80x9cAcylaminoxe2x80x9d refers to the group xe2x80x94C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cAminoacylxe2x80x9d refers to the group xe2x80x94NRC(O)R where each R is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cOxyacylxe2x80x9d refers to the groups xe2x80x94OC(O)-alkyl, xe2x80x94OC(O)-aryl, xe2x80x94C(O)Oxe2x80x94 heteroaryl-, and xe2x80x94C(O)O-heterocyclic where alkyl, ary, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cOxyacylaminoxe2x80x9d refers to the groups xe2x80x94OC(O)NR-alkyl, xe2x80x94OC(O)NRxe2x80x94 substituted alkyl, xe2x80x94OC(O)NR-aryl, xe2x80x94OC(O)NR-heteroaryl-, and xe2x80x94OC(O)NRxe2x80x94 heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cAminocarboxy estersxe2x80x9d refers to the groups xe2x80x94NRC(O)O-alkyl, xe2x80x94NRC(O)O-substituted alkyl, xe2x80x94NRC(O)O-aryl, xe2x80x94NRC(O)O-heteroaryl, and xe2x80x94NRC(O)O-heterocyclic where R is hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclic and where each of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cArylxe2x80x9d refers to an unsaturated aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like.
Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 and preferably 1 to 3 substituents selected from the group consisting of hydroxy, biotinamidyl, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, acylamino, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic, and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
xe2x80x9cAryloxyxe2x80x9d refers to the group aryl-Oxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
The term xe2x80x9ccarboxy terminal R4 groupxe2x80x9d refers to that R4 group in compounds of formula I which, when n is two, is closest to the X group.
xe2x80x9cCarboxyalkylxe2x80x9d refers to the groups xe2x80x94C(O)O-alkyl and xe2x80x94C(O)O-substituted alkyl where alkyl and substituted alkyl are as defined above.
xe2x80x9cCycloalkylxe2x80x9d refers to cyclic alkyl groups of from 3 to 10 carbon atoms having a single cyclic ring or multiple condensed rings which can be optionally substituted with from 1 to 3 alkyl groups. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
xe2x80x9cCycloalkenylxe2x80x9d refers to cyclic alkenyl groups of from 4 to 8 carbon atoms having a single cyclic ring and at least one point of internal unsaturation which can be optionally substituted with from 1 to 3 alkyl groups. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d refers to fluoro, chloro, bromo and iodo and preferably is either chloro or bromo.
xe2x80x9cHeteroarylxe2x80x9d refers to a monovalent aromatic group of from 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within the ring.
Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic and the like. Preferred substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy.
Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
xe2x80x9cHeteroaryloxyxe2x80x9d refers to the group heteroaryl-Oxe2x80x94 wherein the heteroaryl group is as defined above including optionally substituted heteroaryl groups as also defined above.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d refers to a monovalent (i.e., one point of attachment) saturated or unsaturated group having a single ring or multiple condensed rings, from 1 to 8 carbon atoms and from 1 to 4 hetero atoms selected from nitrogen, sulfur or oxygen within the ring.
Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 4 substituents selected from the group consisting of hydroxy, acyl, alkyl, alkoxy, alkenyl, alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, aminoacyl, aminocarboxy esters, alkaryl, aryl, aryloxy, carboxyl, carboxylalkyl, aminoacyl, cyano, halo, nitro, heteroaryl, heterocyclic, oxyacyl, oxyacylamino, thioalkoxy, substituted thioalkoxy, trihalomethyl, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, aryl,-heteroaryl and heterocyclic, and the like. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heteroaryls include morpholino, piperidinyl, and the like.
Examples of heterocycles and heteroaryls include, but are not limited to, furan, thiophene, thiazole, oxazole, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholino, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.
xe2x80x9cHeterocyclyloxyxe2x80x9d refers to the group heterocyclyl-Oxe2x80x94 wherein the heterocyclic group is as defined above including optionally substituted heterocyclic groups as also defined above.
xe2x80x9cOxyacylxe2x80x9d refers to the groups xe2x80x94OC(O)-alkyl, xe2x80x94OC(O)-aryl, xe2x80x94C(O)Oxe2x80x94 heteroaryl-, and xe2x80x94C(O)O-heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cOxyacylaminoxe2x80x9d refers to the groups xe2x80x94OC(O)NH-alkyl, xe2x80x94OC(O)NHxe2x80x94 substituted alkyl, xe2x80x94OC(O)NH-aryl, xe2x80x94OC(O)NH-heteroaryl-, and xe2x80x94OC(O)NHxe2x80x94 heterocyclic where alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
xe2x80x9cThiolxe2x80x9d refers to the group xe2x80x94SH.
xe2x80x9cThioalkoxyxe2x80x9d refers to the group xe2x80x94S-alkyl.
xe2x80x9cSubstituted thioalkoxyxe2x80x9d refers to the group xe2x80x94S-substituted alkyl.
xe2x80x9cThioaryloxyxe2x80x9d refers to the group aryl-Sxe2x80x94 wherein the aryl group is as defined above including optionally substituted aryl groups also defined above.
xe2x80x9cThioheteroaryloxyxe2x80x9d refers to the group heteroaryl-Sxe2x80x94 wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
xe2x80x9cResidues of naturally occurring amino acidsxe2x80x9d refer to the residues of those 20 xcex1-amino acids found in nature which are incorporated into protein by specific recognition of the charged tRNA molecule with its cognate mRNA codon in humans.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to pharmaceutically acceptable salts of a compound of Formula I which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
The compounds of the invention are readily prepared via several divergent synthetic routes with the particular route selected relative to the ease of compound preparation, commercial availability of starting materials, etc.
A first synthetic method involves conventional coupling of an acetic acid derivative with a primary amine of an esterified amino acid as shown in reaction (1) below: 
wherein R1, R2, R3, Xxe2x80x2 and Xxe2x80x3 are as defined above, and X is either oxygen or xe2x80x94NHxe2x80x94.
Reaction (1) merely involves coupling of a suitable acid derivative 1 with the primary amine of amino acid ester 2 under conditions which provide for the N-acetyl derivative 3S. This reaction is conventionally conducted for peptide synthesis and synthetic methods used therein can also be employed to prepare the N-acetyl amino acid esters 3 of this invention. For example, well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Alternatively, the acid halide of compound 1 can be employed in reaction (1) and, when so employed, it is typically employed in the presence of a suitable base to scavenge the acid generated during the reaction. Suitable bases include, by way of example, triethylamine, diisopropylethylamine, N-methylmorpholine and the like.
Reaction (1) is preferably conducted at from about 0xc2x0 C. to about 60xc2x0 C. until reaction completion which typically occurs within 1 to about 24 hours. Upon reaction completion, N-acetyl amino acid ester 3 is recovered by conventional methods including precipitation, chromatography, filtration and the like or alternatively is hydrolyzed to the corresponding acid without purification and/or isolation other than conventional work-up (e.g., aqueous extraction, etc.). Alternatively, the synthesis described above in reaction (1) can be conducted on the amino acid (XR3=OH) and subsequent to N-acetyl formation as described above.
In any event, if an N-acetyl amino acid ester is formed, it is converted to the corresponding acid prior to the coupling step with another amino acid ester/amide, HNHCR4R5C(O)Y. Coupling is accomplished using well known peptide coupling chemistry with well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. which can be used to facilitate coupling. The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like.
Such coupling yields compounds of formula I where n is 1. The synthesis of compounds of formula I where n is 2 is accomplished via a second coupling reaction. Specifically, in the first coupling reaction, HNHCR4R5C(O)Y is selected to be an amino acid ester. That is to say that Y is xe2x80x94O-alkyl. After coupling, the ester is hydrolyzed via conventional conditions well known in the art to provide for the corresponding carboxylic acid which can now be used to couple a second amino acid ester/amide.
In reaction (1), each of the reagents (compound 1 and amino acid ester 2) are well known in the art with a plurality of each being commercially available.
Alternatively, the compounds of formula I can be prepared by first forming the dipeptide ester and then N-acylating these esters. That is to say that the amino acid ester or amide HNHCR4R5C(O)Y is coupled to the N-blocked amino acid BlockNHCHR2COOH via conventional coupling conditions to provide for the dipeptide BlockNHCHR2C(O)N(H)CR4R5C(O)Y. The blocking group is then removed via conventional conditions to provide for the free amine which is then N-acylated in the manner described above to provide for the compounds of formula I.
After coupling and N-acylation (in whatever order) is complete, the resulting esters and amides can be derivatized via conventional chemistry to provide for derivatives of the synthesized compounds. For example, conventional reduction of a terminal ester group with lithium borohydride leads to the terminal xe2x80x94CH2OH group. Alternatively, an ester group can be converted to a primary amide [xe2x80x94C(O)NH2] by reaction with ammonia in methanol with a catalytic amount of sodium cyanide while heating.
Similarly, reactive functionality which is blocked on, for example, R2, can be deblocked and then derivatized. For example, the a BOC protected amino group (e.g., lysine side chain) can be deblocked after synthesis and the amino group acylated or otherwised derivatized.
Additionally, a terminal ester can be subjected to transesterification techniques to provide for other esters. Numerous techniques are known in the art to effect transesterification and each technique merely replaces one ester group with a different ester group derived from the corresponding alcohol or thioalcohol and, in some cases, a catalyst such as titanium (IV) iso-propoxide is used to facilitate reaction completion. In one technique, the alcohol or thioalcohol is first treated with sodium hydride in a suitable diluent such as toluene to form the corresponding sodium alkoxide or thioalkoxide which is then employed to effect transesterification. The efficiency of this technique makes it particularly useful with high boiling and/or expensive alcohols or thioalcohols.
In another transesterification technique, the ester to be transesterified is placed in a large excess of the alcohol or thioalcohol which effects transesterification. A catalytic amount of sodium hydride is then added and the reaction proceeds quickly under conventional conditions to provide the desired transesterified product. Because this protocol requires the use of a large excess of alcohol or thioalcohol, this procedure is particularly useful when the alcohol or thioalcohol is inexpensive.
Transesterification provides a facile means to provide for a multiplicity of different ester substituents on the compounds of formula I above. In all cases, the alcohols and thioalcohols employed to effect transesterification are well known in the art with a significant number being commercially available.
Other methods for preparing the esters of this invention include, by way of example, first hydrolyzing the ester to the free acid followed by O-alkylation with a halo-R3 group in the presence of a base such as potassium carbonate. Alternatively, for esterification procedures for alcohols containing an ester group can be achieved by using the methods of Losse, et al.11.
The compounds described herein can also be prepared by use of polymer supported forms of carbodiimide peptide coupling reagents. A polymer supported form of EDC, for example, has been described (Tetrahedron Letters, 34(48), 7685 (1993))10. Additionally, a new carbodiimide coupling reagent, PEPC, and its corresponding polymer supported forms have been discovered and are very useful for the preparation of the compounds of the present invention.
Polymers suitable for use in making a polymer supported coupling reagent are either commercially available or may be prepared by methods well known to the artisan skilled in the polymer arts. A suitable polymer must possess pendant sidechains bearing moieties reactive with the terminal amine of the carbodiimide. Such reactive moieties include chloro, bromo, iodo and methanesulfonyl. Preferably, the reactive moiety is a chloromethyl group. Additionally, the polymer""s backbone must be inert to both the carbodiimide and reaction conditions under which the ultimate polymer bound coupling reagents will be used.
Certain hydroxymethylated resins may be converted into chloromethylated resins useful for the preparation of polymer supported coupling reagents. Examples of these hydroxylated resins include the 4-hydroxymethylphenylacetamidomethyl resin (Pam Resin) and 4-benzyloxybenzyl alcohol resin (Wang Resin) available from Advanced Chemtech of Louisville, Ky., USA (see Advanced Chemtech 1993-1994 catalog, page 115). The hydroxymethyl groups of these resins may be converted into the desired chloromethyl groups by any of a number of methods well known to the skilled artisan.
Preferred resins are the chloromethylated styrene/divinylbenzene resins because of their ready commercial availability. As the name suggests, these resins are already chloromethylated and require no chemical modification prior to use. These resins are commercially known as Merrifield""s resins and are available from Aldrich Chemical Company of Milwaukee, Wis., USA (see Aldrich 1994-1995 catalog, page 899). Methods for the preparation of PEPC and its polymer supported forms are outlined in the following scheme. 
Such methods are describe more fully in U.S. patent application Ser. No. 60/019,790 filed Jun. 14, 1996 which application is incorporated herein by reference in its entirety. Briefly PEPC is prepared by first reacting ethyl isocyanate with 1-(3-aminopropyl)pyrrolidine. The resulting urea is treated with 4-toluenesulfonyl chloride to provide PEPC. The polymer supported form is prepared by reaction of PEPC with an appropriate resin under standard conditions to give the desired reagent.
The carboxylic acid coupling reactions employing these reagents are performed at about ambient temperature to about 45xc2x0 C., for from about 3 to 120 hours. Typically, the product may be isolated by washing the reaction with CHCl3 and concentrating the remaining organics under reduced pressure. As discussed supra, isolation of products from reactions where a polymer bound reagent has been used is greatly simplified, requiring only filtration of the reaction mixture and then concentration of the filtrate under reduced pressure.
Still other methods for the preparation of esters are provided in the examples below.
Compounds where X is xe2x80x94CR6R6Yxe2x80x2 are readily prepared by coupling, e.g., an amino alcohol H2NCR4R5CR6R6OH, to the carboxyl group of R1ZCXxe2x80x2Xxe2x80x3C(O)NHCHR2C(O)OH under standard coupling conditions well known in peptide coupling chemistry which can use well known coupling reagents such as carbodiimides with or without the use of well known additives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, etc. If necessary, well known blocking groups on Yxe2x80x2 can be employed to protect the group during coupling. Such blocking groups are particularly desirable when Yxe2x80x2 is an amino group.
The reaction is conventionally conducted in an inert aprotic polar diluent such as dimethylformamide, dichloromethane, chloroform, acetonitrile, tetrahydrofuran and the like. Upon reaction completion, any blocking groups on Yxe2x80x2 are selectively removed to provide for the desired compound.
When Yxe2x80x2 is xe2x80x94OH or xe2x80x94SH, post-synthetic conversion of these groups to the corresponding esters (i.e., xe2x80x94OC(O)R7), disulfides (i.e., xe2x80x94SSR7) and xe2x80x94SSC(O)R7 groups is accomplished using well known chemistry. For example, ester synthesis requires only reaction with a suitable acid such as acetic acid (R7=methyl), acid halide (e.g., acid chloride) or acid anhydride under suitable esterification conditions.
When one of R6 is hydrogen, post-synthetic oxidation of the xe2x80x94CHR6OH group leads to the ketone derivatives. Alternatively, such ketones can be prepared by coupling the suitable aminoketone HCl salt with the terminal carboxyl group of the amino acid as illustrated in Example 168 below.
In these synthetic methods, the starting materials can contain a chiral center (e.g., alanine) and, when a racemic starting material is employed, the resulting product is a mixture of R,S enatiomers. Alternatively, a chiral isomer of the starting material can be employed and, if the reaction protocol employed does not racemize this starting material, a chiral product is obtained. Such reaction protocols can involve inversion of the chiral center during synthesis.
Accordingly, unless otherwise indicated, the products of this invention are a mixture of R,S enatiomers or diasteriomers. Preferably, however, when a chiral product is desired, the chiral product corresponds to the L-amino acid derivative. Alternatively, chiral products can be obtained via purification techniques which separate enatiomers from a R,S mixture to provide for one or the other stereoisomer. Such techniques are well known in the art.
When employed as pharmaceuticals, the compounds of formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
This invention also includes pharmaceutical compositions which contain, as the active ingredient, one or more of the compounds of formula I above associated with pharmaceutically acceptable carriers. In making the compositions of this invention, the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient. The term xe2x80x9cunit dosage formsxe2x80x9d refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Preferably, the compound of formula I above is employed at no more than about 20 weight percent of the pharmaceutical composition, more preferably no more than about 15 weight percent, with the balance being pharmaceutically inert carrier(s).
The active compound is effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It, will be understood, however, that the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient""s symptoms, and the like.
For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of the present invention.
The tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which deliver the formulation in an appropriate manner.
The following formulation examples illustrate the pharmaceutical compositions of the present invention.
Hard gelatin capsules containing the following ingredients are prepared:
The above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
A tablet formula is prepared using the ingredients below:
The components are blended and compressed to form tablets, each weighing 240 mg.
A dry powder inhaler formulation is prepared containing the following components:
The active ingredient is mixed with the lactose and the mixture is added to a dry powder inhaling appliance.
Tablets, each containing 30 mg of active ingredient, are prepared as follows:
The active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly. The solution of polyvinyl-pyrrolidone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve. The granules so produced are dried at 50xc2x0 to 60xc2x0 C. and passed through a 16 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg.
Capsules, each containing 40 mg of medicament are made as follows:
The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 150 mg quantities.
Suppositories, each containing 25 mg of active ingredient are made as follows:
The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
Suspensions, each containing 50 mg of medicament per 5.0 ml dose are made as follows:
The active ingredient, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalline cellulose and sodium carboxymethyl cellulose in water. The sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
The active ingredient, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 560 mg quantities.
A subcutaneous formulation may be prepared as follows:
A topical formulation may be prepared as follows:
The white soft paraffin is heated until molten. The liquid paraffin and emulsifying wax are incorporated and stirred until dissolved. The active ingredient is added and stirring is continued until dispersed. The mixture is then cooled until solid.
Another preferred formulation employed in the methods of the present invention employs transdermal delivery devices (xe2x80x9cpatchesxe2x80x9d). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. No. 5,023,252, issued Jun. 11, 1991, herein incorporated by reference. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.
Frequently, it will be desirable or necessary to introduce the pharmaceutical composition to the brain, either directly or indirectly. Direct techniques usually involve placement of a drug delivery catheter into the host""s ventricular system to bypass the blood-brain barrier. One such implantable delivery system used for the transport of biological factors to specific anatomical regions of the body is described in U.S. Pat. No. 5,011,472 which is herein incorporated by reference.
Indirect techniques, which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hydrophilic drugs into lipid-soluble drugs. Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more lipid soluble and amenable to transportation across the blood-brain barrier. Alternatively, the delivery of hydrophilic drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.
Other suitable formulations for use in the present invention can be found in Remington""s Pharmaceutical Sciences, Mace Publishing Company, Philadelphia, Pa., 17th ed. (1985).
The compounds and pharmaceutical compositions of the invention are useful in inhibiting xcex2-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer""s disease in mammals including humans.
As noted above, the compounds described herein are suitable for use in a variety of drug delivery systems described above. Additionally, in order to enhance the in vivo serum half-life of the administered compound, the compounds may be encapsulated, introduced into the lumen of liposomes, prepared as a colloid, or other conventional techniques may be employed which provide an extended serum half-life of the compounds. A variety of methods are available for preparing liposomes, as described in, e.g., Szoka, et al., U.S. Pat. Nos. 4,235,871, 4,501,728 and 4,837,028 each of which is incorporated herein by reference.
The amount of compound administered to the patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions are administered to a patient already suffering from AD in an amount sufficient to at least partially arrest further onset of the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as xe2x80x9ctherapeutically effective dose.xe2x80x9d Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the degree or severity of AD in the patient, the age, weight and general condition of the patient, and the like. Preferably, for use as therapeutics, the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
In prophylactic applications, compositions are administered to a patient at risk of developing AD (determined for example by genetic screening or familial trait) in an amount sufficient to inhibit the onset of symptoms of the disease. An amount adequate to accomplish this is defined as xe2x80x9cprophylactically effective dose.xe2x80x9d
Amounts effective for this use will depend on the judgment of the attending clinician depending upon factors such as the age, weight and general condition of the patient, and the like. Preferably, for use as prophylactics, the compounds described herein are administered at dosages ranging from about 1 to about 500 mg/kg/day.
As noted above, the compounds administered to a patient are in the form of pharmaceutical compositions described above. These compositions may be sterilized by conventional sterilization techniques, or may be sterile filtered. The resulting aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 and 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.